Substituted pyridines are of interest as intermediates in the synthesis of naphthyridine antibacterial agents. 2,6-Dichloro-5-fluoronicotinic acid and 2,6-dichloro-5-fluoronicotinoyl chloride are of particular interest as key intermediates in the synthesis of naphthyridine antibacterial agents as disclosed in European Published Patent Applications 0132,845, 0160,578, 0153,580 and U.S. Pat. Nos. 4,840,954, 4,649,144, and 4,616,019.
A process for preparing 2,6-dichloro-5-fluoronicotinic acid is disclosed in European Published Patent Application 0333,020. However, this process suffers from several major disadvantages. In our hands the conversion of 2,6-dihydroxy-3-cyano-5-fluoropyridine to 2,6-dichloro-3-cyano-5-fluoropyridine using phosphorus oxychloride and phosphorus pentachloride produces 2,4,6-trichloro-3-cyano-5-fluoropyridine as a byproduct. This results a lower yield of the desired 2,6-dichloro-3-cyano-5-fluoropyridine and especially after the hydrolysis the products of this trichloronitrile contaminate the desired nicotinic acid product. As a result, additional purification procedures are required to remove the trichloronitrile byproduct. Finally, another major drawback is the mediocre overall yield (40%-45%) in converting 2,6-dihydroxy-3-cyano-5-fluoropyridine to 2,6-dichloro-5-fluoronicotinic acid. This may be an inherent problem in hydrolyzing the 2,6-dichloro-3-cyano-5-fluoropryridine. E. P. Oliveto states "the hydrolysis of chlorocyanopyridine to chloropyridine acids cannot be considered a generally useful reaction because 2 and 4 halogens are easily hydrolyzed" (see The Chemistry of Heterocyclic Compounds, Pyridine and its Derivatives, Part III, Weissberger, A (Ed.) Interscience Publishers, New York, N.Y. 1962:244).
Thus, we have surprisingly and unexpectedly found that a 2,6-dihydroxy-5-fluoronicotinate can be converted with phosphorus oxychloride in the presence of a lithium reagent to 2,6-dichloro-5-fluoronicotinoyl chloride which is subsequently converted to 2,6-dichloro-5-fluoronicotinic acid.
The object of the present invention is an improved process for preparing 2,6-dichloro-5-fluoronicotinic acid and 2,6-dichloro-5-fluoronicotinoyl chloride by using a novel synthetic scheme.
The present method utilizes inexpensive starting materials, proceeds in fewer steps, and affords higher yields compared to the previous methods. In addition, the present process obviates the need for phosphorus pentachloride with its concomitant overchlorination tendencies (see Mosher HS in Elderfield's Heterocyclic Compounds, John Wiley and Sons, Inc., New York, N.Y., 1950;1:514) and eliminates the need for carrying out a hydrolysis reaction under drastic conditions on a substrate with sensitive functionality.